The present invention relates to a method for the treatment or prevention of Flavivirus infections using nucleoside analogues.
Hepatitis is a disease occurring throughout the world. It is generally of viral nature, although there are other causes known. Viral hepatitis is by far the most common form of hepatitis. Nearly 750,000 Americans are affected by hepatitis each year, and out of those, more than 150,000 are infected with the hepatitis C virus (HCV).
HCV is a positive-stranded RNA virus belonging to the Flaviviridae family and has closest relationship to the pestiviruses that include hog cholera virus and bovine viral diarrhea virus (BVDV). HCV is believed to replicate through the production of a complementary negative-strand RNA template. Due to the lack of an efficient culture replication system for the virus, HCV particles were isolated from pooled human plasma and shown, by electron microscopy, to have a diameter of about 50-60 nm. The HCV genome is a single-stranded, positive-sense RNA of about 9,600 bp coding for a polyprotein of 3009-3030 amino-acids, which is cleaved co- and post-translationally by cellular and two viral proteinases into mature viral proteins (core, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). It is believed that the structural proteins, E1 and E2, the major glycoproteins are embedded into a viral lipid envelop and form stable heterodimers. It is also believed that the structural core protein interacts with the viral RNA genome to form the nucleocapsid. The nonstructural proteins designated NS2 to NS5 include proteins with enzymatic functions involved in virus replication and protein processing including a polymerase, protease and helicase.
The main source of contamination with HCV is blood. The magnitude of the HCV infection as a health problem is illustrated by the prevalence among high-risk groups. For example, 60% to 90% of hemophiliacs and more than 80% of intravenous drug abusers in western countries are chronically infected with HCV. For intravenous drug abusers, the prevalence varies from about 28% to 70% depending on the population studied. The proportion of new HCV infections associated with post-transfusion has been markedly reduced lately due to advances in diagnostic tools used to screen blood donors.
The only treatment currently available for HCV infection is interferon-xcex1 (IFN-xcex1). However, according to different clinical studies, only 70% of treated patients normalize alanine aminotransferase (ALT) levels in the serum and after discontinuation of IFN, 35% to 45% of these responders relapse. In general, only 20% to 25% of patients have long-term responses to IFN. Clinical studies have shown that combination treatment with IFN and ribavirin (RIBA) results in a superior clinical response than IFN alone. Different 30 genotypes of HCV respond differently to IFN therapy, genotype 1b is more resistant to IFN therapy than type 2 and 3.
There is therefore a great need for the further development of anti-viral agents.
The present invention relates to a method for the treatment or prevention of Flavivirus infections in a host comprising administering a therapeutically effective amount of a compound having the formula I or a pharmaceutically acceptable salt thereof: 
wherein
B is chosen from a purine, a pyrimidine or an analogue thereof;
Ra is chosen from H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, and 
xe2x80x83wherein each Rc are independently chosen from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl and an hydroxy protecting group; and
Z is halogen or ORb, wherein Rb is chosen from of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 acyl, or an hydroxy protecting group
D1 and D2 are independently selected from N3, F, or H , D1 and D2 can also be joined to be chosen from C3-cycloalkyl, xe2x80x94xe2x95x90CH2, or xe2x80x94xe2x95x90CF2, and
wherein said compound is in the form of a single enantiomer or a mixture thereof including racemic mixtures;
with the proviso that when B is adenine, Z is ORb, D1 is H, D2 is H and Rb is H, Ra is not triphosphate or H.
In another aspect, there is provided a pharmaceutical formulation comprising the compounds of the invention in combination with a pharmaceutically acceptable carrier or excipient.
Still another aspect, there is provided a method for treating or preventing a viral infection in a host comprising administering a combination comprising at least one compound according to formula I and at least one further therapeutic agent.
In another aspect of the invention is the use of a compound according to formula I, for the preparation of a medicament for treating or preventing a viral infections in a host.